Crosstalk between YY1 and lncRNAs in cancer: A review

Transcription factor YY1 is an important regulator of many pathways in tumor cell growth, prognosis, epithelial-mesenchymal transition, invasion, and resistance to chemotherapy. These effects lead to upregulation of YY1 associated with poor outcomes in many tumors. Growing research evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the regulatory network of YY1. YY1 can regulate lncRNA, and serve as the regulatory molecule of YY1, and lncRNA and YY1 even form a feedback loop. In this review, we summarize the relevant mechanisms of the interaction between YY1 and noncoding RNAs during tumor progression, which will provide a possible theoretical basis for the clinical treatment of tumors.


Introduction
The transcription factor, YY1, is a zinc finger DNA-binding protein in the Gli-Kruppel family, which can regulate gene expression according to chaperone protein, promoter status and chromatin structure. [1] YY1 can interact with a variety of transcriptional regulators, including C-MYC, NOTCH, and YY1-related factors, and is involved in about 10% of the transcriptional control of mammalian genomes. [1,2] YY1 can regulate transcription through replacement, functional interference, chromatin remodeling and induction of cofactor recruitment. [3] YY1 has been proven to be abnormally expressed in many tumors and is associated with poor prognosis in patients. YY1 has been identified to be mainly involved in tumor cell growth, survival, epithelial-mesenchymal transformation, metastasis, and chemotherapy resistance. [4] However, whether YY1 promotes or inhibits tumor growth is still controversial at this stage. For example, Zhang et al found that YY1 was highly expressed in pancreatic cancer compared with normal pancreatic tissues, and high overexpression of YY1 also predicted better survival outcomes in patients with pancreatic cancer. YY1 was also confirmed to inhibit the growth and metastasis of pancreatic cancer cells in vivo and in vitro. [5] However, in melanoma, the increase of YY1 promotes melanoma metastasis, and YY1 can promote the proliferation, cell cycle progression, migration and invasion of melanoma cells. [6] The molecular mechanism of the apparent contradictory effects of YY1 in tumors is still unclear, but it can be seen from the existing research results that this opposite regulatory state mainly depends on different tumor cell types.
With the rapid development of high-throughput technologies, we know from sequencing that protein-coding genes make up less than 2% of the total human genome, while most nucleotide sequences are transcribed by non-coding RNAs. [7] Non-coding RNAs can also be divided into housekeeping RNAs (such as rRNA and tRNA) and regulatory RNAs (such as microRNAs, long non-coding RNAs [lncRNAs], and circRNAs). Non-coding RNAs with a length of more than 200 nucleotides are lncRNAs. [8] lncRNAs are mainly involved in chromatin dynamics, gene expression, cell growth, differentiation and development, and transcriptome analysis results of sequencing showed that 1000 of lncRNAs showed abnormal expression or mutation in various tumors. [9] lncRNAs play a key role in human tumors, but the specific regulatory mechanism of their involvement in tumors remains unclear. Recent studies have shown that lncRNAs can regulate YY1 network to control tumor growth. YY1 not only regulates the expression of lncRNAs (Fig 1), but also is an important downstream effector of lncRNAs. In this review, we mainly discuss the mechanism of crosstalk between YY1 and lncRNAs.

YY1 and lncRNAs
LncRNAs not only regulate chromatin remodeling and recruit transcription factors, but also may be involved in mRNA stability, translation, protein stability or localization. Recent studies have shown that YY1 has been confirmed to play a key role in lncRNAs regulatory network. In Table 1 and Table 2, we summarized the lncRNAs related to YY1 regulatory network. YY1-regulated lncRNAs promote tumor progression through multiple mechanisms. lncRNA PVT1 is involved in the progression of various tumors, including non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, breast cancer and glioma. [11] Researchers found that YY1 can directly bind to the promoter region of PVT1 to promote tumor growth in lung cancer. [12] Similar studies have shown that UPLA1 is associated with the progression and prognosis of lung cancer. It was determined that YY1 could bind to UPLA1 at sites 1: 280 to 291, 2: 633 to 644, 3: 636 to 641 and 4: 912 to 923, and reverse regulate the expression of lncRNA-UPLA1. [13] miRNA also participates in YY1-regulated lncRNAs network in lung cancer. YY1-mediated ZFPM2-AS1 promotes down-regulation of miR-3612 activity, while TNF receptor-associated factor 4 (TRAF4) interacts with miR-3612 in lung cancer. [14] YY1induced MCM3AP-AS1 promotes cell proliferation, migration and angiogenesis in lung cancer cells by targeting miR-340-5p/ Karyopherin α 4 axis. Further rescue tests showed that Karyopherin α 4 overexpression attenuates the inhibitory effect of MCM3AP-AS1 silencing on angiogenesis and progression of lung cancer cells. [15] PKMYT1 is a major player in cell cycle regulation and DNA damage recognition and repair in cancer cells. [16] PKMYT1AR induced by YY1 directly interacts with miR-485-5p to inhibit the expression of oncogene PKMYT1. PKMYT1 promotes the dryness of cancer stem cells through β-catenin ubiquitin degradation, leading to lung cancer  progression. [17] In additional, LINC01089 inhibited by YY1 competes with endogenous RNA of miR-301b-3p to promote hydroxyprostaglandin dehydrogenase expression. [18] 2.1.2. YY1-regulated lncRNAs and breast cancer. Breast cancer is one of the most common cancers in women, and the number of new cases of cancer continues to rise gradually each year. [19] Studies have shown that binding YY1 to LINC00152 promoter blocks LINC00152 transcription. The up-regulated LINC00152 significantly promoted the ubiquitination and degradation of PTEN protein in breast cancer. [20] YY1 promote the transcription of Kcnq1to1, which mediated PTEN methylation through DNMT1, thereby inhibiting the expression of PTEN in triple negative breast cancer. [21] PTEN is a tumor suppressor gene in breast cancer and is frequently mutated/lost in tumors. [22] miRNA also participates in YY1-regulated lncRNAs network in breast cancer. YY1 binds to LINC00673 promoter to increase its cis-transcription. LINC00673 promotes tumor cell growth by regulating breast cancer cell cycle and apoptosis. This result was achieved mainly by sponging miR-515-5p to act as ceRNA to regulate MARK4 (Microtubule affinity regulating kinase 4) expression and thereby inhibit Hippo signaling pathway. [23] DUXAP8 acts as a miR-29a-3p sponge to promote the expression of the downstream gene SAPCD2 (Suppressor APC Domain Containing 2) in breast cancer. YY1 promoted the transcriptional activation of DUXAP8. [24] 2.1.3. YY1-regulated lncRNAs and gliomas. Glioma is the most common primary tumor of the central nervous system, and about half of gliomas are diagnosed as glioblastoma, a highly aggressive brain tumor. [25] Aging is an important factor associated with poor prognosis of glioblastoma, and YY1 binds to the promoter domain of TP73-AS1 in the aging brain to promote its transcription. [26] YY1 promoted the transcription of SNHG5 in glioblastoma, and it was found that SNHG5 could enhance the carcinogenic role of P38/MAPK signaling pathway in glioblastoma. [27] miRNA also participates in YY1-regulated lncRNAs network in gliomas. LINC00466 is up-regulated and is associated with poor prognosis in gliomas. Silencing LINC00466 inhibited the growth and metastasis of tumor cells and promoted apoptosis. Mechanistically, YY1 can directly bind to the promoter region of LINC00466, which can bind to miR-508 to inhibit its expression and act as an endogenous sponge to regulate the expression of CHK1 (checkpoint kinase I). [28] CHK1 can participate in cell DNA replication, mitosis process and DNA repair. [29] YY1-promoting transcriptional SNHG17 interacts with miR-506-3p to promote the expression of CTNNB1(Catenin β1), which is an important protein in activating Wnt/β-catenin signaling pathway in gliomas. [30] YY1 promoted up-regulation of PCAT6 in glioblastoma, and PCAT6 promoted downstream insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) protein expression in a competitive endogenous RNA manner through miR-513. [31]  IGF2BP1 is involved in tumor cell proliferation, metastasis and chemical resistance. [32] 2.1.4. YY1-regulated lncRNAs and colorectal cancer. Colorectal cancer remains one of the most common cancers with a global disease burden, with one of the highest morbidity and mortality rates among cancers. [33] luciferase reporter gene detection showed that YY1 had strong activity on the ARAP1-AS1 promoter. YY1 promoted the expression of ARAP1-AS1, and promoted the proliferation and metastasis of tumor cells through Wnt/β-catenin signaling pathway. [34] The study confirmed that the variation of GAS5 promoter RS55829688 was related to the risk of colorectal cancer, and the combination of YY1 and GAS5 negatively regulated the expression of GAS5. [35] GAS5 inhibits the proliferation and metastasis of colorectal cancer by regulating the degradation of YAP phosphorylation, and is negatively regulated by m6A reader YTHDF3. [36] Further studies found that there was also a regulatory relationship between the YY1-regulated lncRNAs network and miRNA in colorectal cancer. DDX11-AS1 promoted by YY1 promotes tumor cell proliferation, migration and invasion and inhibits apoptosis by targeting the miR-873/ CLDN7 axis. [37] In addition, YY1 promoted the proliferation and metastasis and increased the inhibition of apoptosis through LINC01224/miR-485-5p/MYO-6 axis. [38] 2.1.5. YY1-regulated lncRNAs and hepatocellular carcinoma. Hepatocellular carcinoma is a high incidence tumor in the world. Despite the continuous improvement of medical technology in recent years, the mortality rate of hepatocellular carcinoma is still increasing due to the fact that most of the patients detected are in advanced stage. [39] YY1 binds to the MER52A promoter and promotes transcription. The MER52A promotes hepatocellular carcinoma cell migration and invasion by stabilizing p120-catenin and activating the p120-catenin/ Rac1/Cdc42 axis. [40] YY1 directly binds to the promoter of CASC11, and YY1 knockdown inhibits the expression of CASC11. CASC11 promotes hepatocellular carcinoma growth through EIF4A3 mediated E2F1. [41] Up-regulated LINC00205 is positively correlated with grade and leads to poor prognosis of hepatocellular carcinoma, and LINC00205 knockout promotes cell cycle arrest and apoptosis of tumor cells in G0/G1 phase. Further study of the mechanism found that LINC00205 induced by YY1 directly binds to miR-26a-5p to promote CDK6 expression and promote the progression of HCC cells. [42] 2.1.6. YY1-regulated lncRNAs and pancreatic cancer. Pancreatic cancer has become the third leading cause of tumor-related death in the United States, and new cases and deaths continue to increase each year. [43] LINC00842 participates in metabolic remodeling in pancreatic cancer cells and is deacetylated by SIRT1 (Sirtuin 1) by inhibiting the acetylation of Peroxisome proliferator-activated receptor-γ coactivator. Upstream mechanism studies have shown that exposure to YY1 in high glucose levels promotes the expression of LINC00842 in tumor cells. [44] YY1 binds to the DICER1-AS1 promoter to promote its transcription, and the up-regulated DICER1-AS1 acts as a sponge for miR-5586-5p and inhibits the expression of glycolysis genes, including LDHA, HK2, PGK1 and SLC2A1. [45] LINC01133 regulates a variety of malignancies, including cancers of the digestive system, female reproductive system, respiratory system and urinary system. [46] LINC01133 can recruit YY1 on its promoter. Upregulated LINC01133 directly interacts with miR-199b-5p to target the myelin regulatory factor, thereby promoting pancreatic cancer growth and metastasis. [47] 2.1.7. YY1-regulated lncRNAs and gynecologic related tumor. Ovarian cancer is usually detected in patients at an advanced stage and is the most common cause of gynecological cancer death, which is often associated with recurrence. It is therefore important to identify specific mechanisms for the progression of ovarian cancer. [48] PART1 can promote the proliferation and metastasis of ovarian cancer cells, which can improve the potential targets for the treatment of ovarian cancer. YY1-induced PART1 directly binds to the miR-512-3p target and regulates the CHRAC1 (Chromatin Accessibility Complex Subunit 1), thereby increasing the cisplatin resistance of ovarian cancer. [49] Cervical cancer is a common gynecological tumor and is closely related to high risk subtypes of human papillomavirus (HPV). [50] High-risk-HPV infection is an important factor causing cervical cancer in women. lnc-FANCI-2 is transcribed and selectively spliced by 2 alternative promoters and polyadenylated at 1 of 2 alternative poly (A) sites. YY1 can interact with E7 CR3 core gene to trans-activate the promoter of lnc-FANCI-2. In addition, HPV18 promoted YY1 expression by reducing the 3' untranslated region of miR-29a targeted YY1 mRNA. [51] Endometriosis has been considered as a precursor to neoplasms associated with endometriosis. [52] In endometriosis, the PROMO and AnimalTFDB databases predict that lncRNAs (MALAT1, NEAT1, SNHG22, and XIST) may interact with YY1. [53] 2.1.8. YY1-regulated lncRNAs and other malignant tumors. With the confirmation of YY1 and lncRNAs as tumor regulatory networks, more and more researchers have conducted further studies on their crosstalk mechanism and found that YY1regulated lncRNAs are involved in the regulation of esophageal squamous cell carcinoma, laryngeal squamous cell carcinoma, nasopharyngeal carcinoma, cholangiocarcinoma, gastric cancer, bladder cancer, melanoma, prostate cancer, acute leukemia and osteosarcoma. in esophageal squamous cell carcinoma, YY1 has been confirmed to bind to the hypomethylation promoter region of ESCCAL-1, [54] and YY1-induced BLACAT1 was able to compete with PD-L1 for binding to miR-5590-3p in esophageal cancer cells. [55] FOXP4-AS1 can up-regulate FOXP4 expression and promote the proliferation of esophageal squamous cell carcinoma by sponging miR-3184-5p, and YY1 can promote the activation transcription of FOXP4-AS1. [56] YY1 promotes the progress of laryngeal squamous cell carcinoma and telomerase activity by inhibiting the stability of GAS5dependent p53 or reducing the stability of p53 by binding to P300. [57] Chen et al found that TTN-AS1 activated by YY1 transcription interacts with miR-876-5p and UPF1 to promote the expression of NETO2, thereby promoting the proliferation and metastasis of nasopharyngeal carcinoma. [58] As an oncogene of cholangiocarcinoma, PCAT1 can be activated and transcribed by YY1. PCAT1 mainly exists in the cytoplasm and promotes the expression of BCL3 through the PCAT1/miR-216A-3p axis. [59] In addition, YY1 promotes transcriptional activation of LINC00667, and then LINC00667 promotes the expression of PDK1 by binding to miR-200c-3p to promote the progress of cholangiocarcinoma. [60] SNHG12 negatively regulated by YY1 promotes the progression of gastric cancer through the miR-218-5p/YWHAZ axis and the stabilization of CTNNB1 protein by promoting the activity of β-catenin. [61] Zhang et al found that YY1 promotes the transcriptional activation of PSMA3-AS1, and targets miR-214-5p to promote the expression of PD-L1 in bladder cancer cells. [62] YY1 can also promote the transcriptional activity of SNHG8, and then directly interact with miR-656-3p to regulate SERPINE1 mRNA binding protein 1 (SERBP1) in melanoma. [63] Hua et al 's study in prostate cancer showed that the combination of RS 1,16,72,691 and RS 8,87,391 with promoters of transcription factors NKX3.1 and YY1 regulates the expression of short isoform of PCAT19 by regulating the binding of transcriptional activators YY1 to their promoters. The risk variants of RS 1,16,72,691 and RS 8,87,391 attenuated the binding of transcription factors YY1 to the short isoform of PCAT19 promoter, leading to reduced promoter activity but enhanced promoter activity, followed by activation of long www.md-journal.com isoform of PCAT19. [64] YY1 promotes transcription of SNHG5 and regulates angiogenesis of acute leukemia by targeting miR-26b to activate CTGF/VEGFA. [65] YY1 promotes the transcription of TNK2-AS1, thereby promoting osteosarcoma progression through TNK2-AS1/miR-4319/WDR1 axis. [66] YY1 inhibits transcriptional activation of HCG11 by binding to the promoter region of HCG11. HCG11 interacts with downstream molecules miR-942-5p and IGF2BP2 to promote the expression of P27 Kip1, which is an important molecule in the biological function of osteosarcoma. [67] 2.2. LncRNAs regulating YY1 2.2.1. LncRNAs controlling YY1 transcription or translation. In nasopharyngeal carcinoma, some scholars have found that NPCCAT1 directly binds to YY1 mRNA 5'UTR, promotes YY1 mRNA translation. The results of cell biological function showed that YY1 promoted the proliferation and migration of tumor cells. In addition, the results of salvage experiments showed that YY1 knockout on the basis of NPCCAT1 overexpression weakened the effect of NPCCAT1 in promoting tumor growth. [68] In addition, upregulation of TLCD2-1 leads to radiation resistance in colorectal cancer. TLCD2-1 promotes the expression of YY1 mRNA by targeting miR-193A-5p, thus regulating the colorectal cancer immune infiltrating microenvironment. [69] LINC00899 mainly exists in the cytoplasm and is highly expressed, which is associated with poor prognosis in patients. Animal experiments show that LINC00899 promotes tumor growth. miR-744-3p is the downstream gene of LINC00899, and miR-744-3p directly interacts with YY1 to regulate the mRNA expression of YY1. [70] In medulloblastoma, HOTAIR acts as a sponge of miR-1 and miR-206 to promote YY1 mRNA and protein expression. Cell experiments revealed that HOTAIR promoted tumor growth and metastasis of tumor cells and inhibited apoptosis by miR-1/ miR-206-YY1 axis. [71] GACAT1 binds to miR-422a to regulate the expression of YY1 mRNA and protein in NSCLC cells. [72] Finally, the research found that LINC00958 is associated with poor prognosis of breast cancer. m6A-induced LINC00958 acts as a spongiform for miR-378a-3p to target YY1 and promote the progression of breast cancer. [73] These results suggest that lncRNA controls YY1 mRNA stability or translation (Fig 2A). Figure 2A, lncRNA affects YY1 protein stability or activity (Fig 2A). LINC01186 is overexpressed in thyroid papillary carcinoma and blocks tumor suppressor kinase 1 signal transduction by inhibiting the expression of YY1-related proteins. [74] CASC15 promotes YY1-mediated transcriptional regulation of SOX4 promoter and enhances downstream effects of SOX4. [75] In hepatocellular carcinoma, LINC00668 promotes YY1 protein expression by miR-532-5p, thereby accelerating cell proliferation, metastasis, and epithelial-mesenchymal transition processes. [76] TCONS_00012883 is mainly located in the nucleus and interacts with DDX3 to up-regulate target gene MMP1 and promote colorectal cancer progression. Knocking TCONS_00012883 inhibited the enrichment of YY1 on the MMP1 promoter, while lncRNA-TCONS_00012883 overexpression enhanced the enrichment. [77] Wu et al found that LINC00278 is a novel Y-linked lncRNA capable of encoding YY1-binding micropeptide (YY1BM). YY1BM blocks the interaction between YY1 and androgen receptor, thereby inhibiting the expression of eEF2K, while smoking reduces the m6A modification of lLINC00278 and YY1BM translation in esophageal squamous Cell Carcinoma. [78] In small-cell lung cancer, YY1 promotes transcriptional activation of SNHG16, which promotes USP21 expression through miR-4500, and USP21 stabilizes protein levels by deubiquitination of YY1. [79] Another similar study found that SNHG14 silencing can inhibit the protein expression of Cyclin D1 and N-cadherin, and promote the expression of Bax, Cleaved caspase-3 and e-cadherin. Further study of the mechanism found that SNHG14 directly binds to miR-5590-3p, while the 3'UTR of miR-5590-3p can interact with YY1 protein in prostate cancer. [80]

Feedback loops between YY1 and lncRNAs
Some lncRNAs induced by YY1 can also conversely regulate the expression level of YY1 (Fig 2B). Yu et al found that YY1 promoted transcriptional activation of LINC00667 and further regulated the progression of colorectal cancer through downstream target miR-449B-5p. Further mechanism studies found that YY1 overexpression weakened the promoting effect of LINC00667 on colorectal cancer cell growth, and LINC00667 promoted the expression of YY1 mRNA and protein through miR-449b-5p. [81] LINC01578 was shown to be a chromatin binding lncRNA. The study has confirmed that LINC01578 is associated with metastasis and poor prognosis of colorectal cancer, and functional experiments have shown that LINC01578 can promote liver metastasis of colon cancer. Mechanistically, YY1 binds to the promoter of LINC01578 to promote its transcriptional activity, and LINC01578 interacts with EZH2 to recruit it to the NFKBIB promoter, thereby activating NF-κB signal transduction. However, LINC01578 in turn promotes its own promoter activity by activating the NF-κB/YY1 axis. [82] Mechanistically, activation by binding to OIP5-AS1 promoter, and OIP5-AS1 directly targets miR-300. Further studies found that miR-300 targets YY1 to regulate the WNT pathway. The results revealed that OIP5-AS1/miR-300/YY1 axis formed a feedback loop. [83] Up-regulated MIR31HG promotes glycolysis of colorectal cancer, vascular endothelial cell formation, and lung metastasis. Mechanistically, up-regulation of YY1 can promote the transcriptional activity of MIR31HG, and overexpression of MIR31HG can further promote the expression of YY1. [84] LINC01134 knockdown inhibits hepatocellular carcinoma proliferation, metastasis and promotes apoptosis, and inhibits tumor growth in vivo. Further mechanism studies found that YY1 promotes transcription by binding to promoters at sites -773 to -762 upstream of LINC 01134 transcription termination site. LINC01134 acts as a miR-324-5p sponge and interacts with IGF2BP1 to increase the stability of YY1 mRNA expression. Finally, overexpressed YY1 can promote the transcription of LINC01134. The results show that there is a feedback loop between YY1 and LINC01134. [85] LOXL1-AS1 interacts with miR-3614-5p and binds to the target gene YY1 in hepatocellular carcinoma. Further study of the mechanism found that YY1 also promoted the transcriptional activity of LOXL1-AS1. [86] Silencing LINC02532 enhances radiosensitivity of clear cell renal cell carcinoma by inhibiting DNA double-strand breaks repair. Mechanistically, on the 1 hand, YY1 promotes its transcription by binding to LINC02532 promoter, and on the other hand, LINC02532 interacts with miR-654-5p to promote YY1 expression. [87] KB-1460A1.5 can affect the metabolism of amino acids in glioma. The KB-1460A1.5/miR-130a-3p axis regulates the expression of the transcription factor YY1 through the key gene TSC1 of the mTOR pathway, and the expressed YY1 directly binds to the kB-1460A1.5 promoter to feedback and regulate the transcription of KB-1460A1.5. [88]

Conclusions
Many studies have confirmed that YY1 and lncRNAs have close and complex crosstalk, which play a crucial role in tumor progression. YY1 can regulate lncRNAs, and lncRNAs can also serve as the regulatory molecule of YY1, and lncRNAs and YY1 even form a feedback loop. Although we have described the mechanisms related to YY1 and lncRNA network in recent years, the mechanisms still need to be further discussed before we can have a comprehensive and clear understanding of malignant tumor transformation. The research of YY1 in tumor has become more and more mature, but the specificity of its drug is still poor. In principle, loss or recovery of lncRNAs in the YY1 network could be an alternative to YY1 drugs. Therefore, we urgently need to systematically elucidate the mechanism of mutual regulation between YY1 and non-coding RNAs, which will provide a possible theoretical basis for the clinical treatment of tumors.